Reactions of Alkyl Halides

1. Reactions of Alkyl Halides • “Ninety-five percent of the reactions that we see in organic chemistry occur between a nucleophile and an electrophile.” • Klein, D.R., Organic Chemistry as a Second Language, 2004, John Wiley & Sons, Inc. • The alkyl halides undergo a variety of reactions that will help us begin the study of reactions between nucleophiles and electrophiles.

2. Nucleophiles and Electrophiles • Nucleophiles are chemical species with a negative charge or an unbonded pair of electrons. • Nucleophile = Lewis base • Electrophiles are chemical species that can accept an electron pair. • Electrophile = Lewis acid • Being able to draw Lewis structures is vital to understanding the material in this and following units.

3. Nucleophiles and Electrophiles Which species are nucleophiles?

4. Reactions of Alkyl Halides • Alkyl halides undergo a variety of reactions because Cl-, Br-, and I- are good leaving groups. • This makes possible two types of reactions. • Substitution, where a nucleophile replaces the leaving group. • Elimination, where H+ leaves as well and an alkene is formed.

5. Nucleophilic Substitution leaving group

6. Elimination leaving group B:- is a species acting as a base. FYI: Some species can act as both bases and nucleophiles.

7. Kinetics of Substitution Reactions: SN1 and SN2 • There are two different mechanisms by which nucleophilic substitution can happen. • SN1: substitution, nucleophilic, unimolecularrate = k[substrate] • SN2: substitution, nucleophilic, bimolecular rate = k[substrate][nucleophile]

8. SN2 Reaction Mechanism δ- δ- δ- δ+  nucleophile substrate (electrophile) transition state  leaving group product

9. SN2 Reaction Profile rate = k[CH3I][OH-] -EA/RT k = Ae EA

10. SN2 Reactions • SN2 reactions are exothermic. • SN2 reactions are concerted: they occur in a single step as the result of a collision between the nucleophile and the substrate. • The Arrhenius equation shows that the rate constant k is a function of the activation energy EA and the temperature. (True for all reactions.)

11. SN2 Reaction Products from Alkyl Halides - A Partial List R-I alkyl iodide R-OH alcohol R-OR’ ether R-SH thiol R-NH2 amine R-C≡C-R’ alkyne R-CN nitrile R’-COO-R ester What would the starting alkyl halide be? What would the starting nucleophile be?

12. Factors Affecting SN2 Reactions • Strength of the nucleophile • Stronger nucleophiles give faster reactions. • The solvent in which the reaction is run. • Nature of the leaving group • Structure of the substrate • Can the nucleophile easily reach the electropositive C atom? FYI: You will use this template to study many other types of organic reactions.

13. Factors Affecting SN2 Reactions - Strength of the Nucleophile • Look at the nucleophile in terms of the transition state. • Nucleophiles that decrease the energy of the transition state increase the rate of reaction. • A species with a negative charge is a stronger nucleophile than a similar species that is neutral. • OH- is a better nucleophile than H2O. • A base is a better nucleophile than its conjugate acid.

14. Factors Affecting SN2 Reactions - Strength of the Nucleophile • Good nucleophiles must be polarizable. • This facilitates the formation of the partial bond in the transition state and makes EA lower. • Polarizability increases down a group, due to the increase in size and decrease in electronegativity. • I- > Br- > Cl- > F-

15. Factors Affecting SN2 Reactions - Strength of the Nucleophile • Good nucleophiles must be electronegative (we say electron withdrawing), but not too electronegative. • The nucleophile must be able to hold nonbonding electrons, but it must be able to let the electrons go as it forms the bond to the substrate. • F- is a weak nucleophile. • I- is an excellent nucleophile.

16. Strength of some nucleophiles in water or alcohol solvents Strong (CH3CH2)3P: HS- I- (CH3CH2)2NH CN- (CH3CH2)3N: HO- CH3O- Moderate Br- NH3 CH3SCH3 Cl- .. increasing strength Weak CH3COO- F- HOH CH3OH

17. Nucleophilicity vs. Basicity • These terms describe functions. • The nucleophilicity of a species is a kinetic term referring to how fast the species will attack an electrophilic C atom. • The basicity of a species is how well it abstracts a proton H+. This refers to the position of the equilibrium and is a thermodynamic term. • CH3O- or I- : Which is the better base? • Which is the better nucleophile?

18. Factors Affecting SN2 Reactions - Steric Effects on Nucleophilicity • Good nucleophiles must be able to get close enough to form a bond to the electrophilic C atom. • Bulky groups on the nucleophile can hinder this approach.  stronger base stronger nucleophile  Bulky groups don’t affect basicity much.

19. Factors Affecting SN2 Reactions - Solvent Effects • In SN2 reactions, the main effect of the solvent is on nucleophilicity. • Protic solvents such as water and alcohols can solvate nucleophiles through H-bonding. • This solvation impedes the formation of the partial bond in the transition state. These must leave for the reaction to proceed.

20. Factors Affecting SN2 Reactions - Solvent Effects • Polar aprotic solvents such as acetone, THF, and acetonitrile solvate the cation but not the nucleophile. • Polar aprotic solvents enhance nucleophilicity.

21. Factors Affecting SN2 Reactions - the Leaving Group • The leaving group (LG) serves two purposes in an SN2 reaction. • It polarizes the bond that makes the C atom electrophilic. • It carries away a pair of electrons from the electrophilic C atom.

22. Factors Affecting SN2 Reactions - the Leaving Group • A good LG must be: • electron withdrawing, to polarize the bond and make the C atom electrophilic, • polarizable, to stabilize the transition state, and • stable in the solvent (so it cannot be a strong base). Best LGs are neutral species or anions with a stabilized charge. • The first two are the same as for a strong nucleophile, but the last one is not!

23. Good Leaving Groups - Ions that are weak bases Cl- Br- I- sulfonates sulfates phosphates

24. Good Leaving Groups - Molecules that are weak bases alcohols amines phosphines

25. Rotten Leaving Groups - strong bases hydroxide alkoxides amide

26. How to Make a Rotten LG Better • Protonate the LG by acidifying the solution. • Example: Use HBr instead of NaBr to make methyl bromide from methanol. • This turns a poor leaving group (OH-) into a good one (H2O).

27. Factors Affecting SN2 Reactions - Structure of the Substrate • To be a good substrate for SN2 attack, a molecule must have an electrophilic C atom with a good leaving group and which is not too sterically hindered for the nucleophile to attack. • Alkyl halides are not the only substrates for SN2 reactions.

28. Factors Affecting SN2 Reactions - Structure of the Substrate • The substrate is the species undergoing nucleophilic attack. • The substrate contains the electrophilic C and the LG. • Bulky groups on the electrophilic C atom can hinder nucleophilic attack. • Relative rates for SN2: CH3X>1°>2°

29. Factors Affecting SN2 Reactions - Structure of the Substrate • Relative rates for SN2: • CH3X >1°>2° • 3° halides do not react by SN2. 2° halides give much slower SN2 rates due to steric hindrance of the nucleophile. Methyl halides give fastest SN2 rates.

30. Stereochemistry of the SN2 Reaction • Because of the attack from the side opposite the LG, the configuration of the product is inverted around the electrophilic C atom.  (S)-2-bromobutane (R)-2-butanol

31. SN2 Reactions - Summary • The structure of the substrate around the electrophilic C affects the rate: • Relative rates for SN2: CH3X>1°>2°. • The nucleophile should be moderate to strong and not solvated by the solvent. • The LG should be more stable in the solvent than the nucleophile. • The solvent should dissolve the nucleophile but not solvate it…polar aprotic solvents are best. • There will be an inversion of configuration around the electrophilic C.